The primary goal of this proposal is to provide support and continued mentorship, which will facilitate the candidate 's development into an independent scientific investigator. This goal will be achieved through defined coursework, intense mentored research, and at least 75% protected research time. Using this research proposal as a platform, the candidate will gain expertise in a number of fundemental scientific techniques including: murine bone marrow transplantation, development of transgenic animals, controlled exposures to an aersolized environmental toxin, and phenotyping both the physiologic and biologic response in small animals as it relates to human disease. The broad objective of this proposal is to better understand the role of TLR4 (a transmembrane receptor for LPS) in regulating the physiologic and biologic response to inhaled endotoxin (LPS). Endotoxin is important in a number of human pulmonary diseases, including organic dust induced airway disease, pneumonia, acute lung injury, and ARDS. Understanding the basic biology leading to the innate immune response to endotoxin, could have a broad impact on the management of a number of human diseases. This proposal outlines the investigation of the importance of both cell-type specific expression of TLR4 and the biological importance of naturally occuring polymorphisms of human TLR4 to irihaled endotoxin with the following specific aims. Specific Aim 1: Determine whether TLR4 expression by inflammatory cells (macrophages, dendritic, lymphocytes, and neutrophils) or structural cells (airway epithelia, endothelia, and pneumocytes) is sufficient to maintain an intact physiologic and biologic response to inhaled LPS. Specific Aim 2: Determine whether cell specific TLR4 expression by macrophages, neutrophils, or airway epithelial cells is sufficient to maintain an intact physiologic and biologic response to inhaled LPS. Specific Aim 3: Determine the physiologic and biologic importance of polymorphisms in human TLR4 in a murine model to inhaled endotoxin.